Low-rank latent matrix-factor prediction modeling for generalized high-dimensional matrix-variate regression.

Motivated by diagnosing the COVID-19 disease using two-dimensional (2D) image biomarkers from computed tomography (CT) scans, we propose a novel latent matrix-factor regression model to predict responses that may come from an exponential distribution family, where covariates include high-dimensional matrix-variate biomarkers. A latent generalized matrix regression (LaGMaR) is formulated, where the latent predictor is a low-dimensional matrix factor score extracted from the low-rank signal of the matrix variate through a cutting-edge matrix factor model. Unlike the general spirit of penalizing vectorization plus the necessity of tuning parameters in the literature, instead, our prediction modeling in LaGMaR conducts dimension reduction that respects the geometric characteristic of intrinsic 2D structure of the matrix covariate and thus avoids iteration. This greatly relieves the computation burden, and meanwhile maintains structural information so that the latent matrix factor feature can perfectly replace the intractable matrix-variate owing to high-dimensionality. The estimation procedure of LaGMaR is subtly derived by transforming the bilinear form matrix factor model onto a high-dimensional vector factor model, so that the method of principle components can be applied. We establish bilinear-form consistency of the estimated matrix coefficient of the latent predictor and consistency of prediction. The proposed approach can be implemented conveniently. Through simulation experiments, the prediction capability of LaGMaR is shown to outperform some existing penalized methods under diverse scenarios of generalized matrix regressions. Through the application to a real COVID-19 dataset, the proposed approach is shown to predict efficiently the COVID-19.

Nucleolar localization of RAG1 modulates V(D)J recombination activity.

V(D)J recombination assembles and diversifies Ig and T cell receptor genes in developing B and T lymphocytes. The reaction is initiated by the RAG1-RAG2 protein complex which binds and cleaves at discrete gene segments in the antigen receptor loci. To identify mechanisms that regulate V(D)J recombination, we used proximity-dependent biotin identification to analyze the interactomes of full-length and truncated forms of RAG1 in pre-B cells. This revealed an association of RAG1 with numerous nucleolar proteins in a manner dependent on amino acids 216 to 383 and allowed identification of a motif required for nucleolar localization. Experiments in transformed pre-B cell lines and cultured primary pre-B cells reveal a strong correlation between disruption of nucleoli, reduced association of RAG1 with a nucleolar marker, and increased V(D)J recombination activity. Mutation of the RAG1 nucleolar localization motif boosts recombination while removal of the first 215 amino acids of RAG1, required for efficient egress from nucleoli, reduces recombination activity. Our findings indicate that nucleolar sequestration of RAG1 is a negative regulatory mechanism in V(D)J recombination and identify regions of the RAG1 N-terminal region that control nucleolar association and egress.

Incidence and risk factors for retinopathy of prematurity in extreme low birth weight Chinese infants.

The objective of this study is to determine the incidence and risk factors of retinopathy of prematurity (ROP) in extremely low birth weight (ELBW) Chinese infants. A retrospective medical record review of all ELBW (≤1,000 g) neonates screened for ROP from 2007 to 2012 was performed in Hong Kong. ROP screening was conducted at 2 neonatal intensive care units by 3 pediatric ophthalmologists using the Royal College of Ophthalmologists ROP guideline and the International Classification of ROP. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. In 131 ELBW Chinese infants, the mean gestational age (GA) and birth weight (BW) were 27.3 ± 3.3 weeks and 806.9 ± 133.7 g, respectively. The incidence of ROP and Type 1 ROP was 53.4 and 14.5 %, respectively. For ROP, a lighter BW, smaller GA, vaginal delivery, postnatal hypotension, inotrope use, bronchopulmonary dysplasia, surfactant use, invasive mechanical ventilation, and supplementary oxygen were independent risk factors for ROP, while PET was protective (P ≤ 0.02). On multivariate analysis, a smaller GA was a risk factor, while PET and congenital heart disease were protective for ROP development (P ≤ 0.01). For Type 1 ROP, a lighter BW, smaller GA, surfactant use, and invasive mechanical ventilation were independent risk factors for ROP, while PET was protective (P ≤ 0.02). There were no significant covariates on multivariate analysis for Type 1 ROP. In ELBW, preterm Chinese infants, a smaller GA was a risk factor for ROP, while PET and congenital heart disease were protective for ROP development in multivariate analysis.

Differences in risk factors for retinopathy of prematurity development in paired twins: a Chinese population study.

PURPOSE: To determine the differences in risk factors for retinopathy of prematurity (ROP) in paired twins. METHODS: A retrospective medical record review was performed for all paired twins screened for ROP between 2007 and 2012. Screening was offered to very low birth weight (≤ 1500 grams) and preterm (≤ 32 weeks) neonates. Twins 1 and 2 were categorized based on the order of delivery. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. RESULTS: In 34 pairs of Chinese twins, the mean gestational age (GA) was 30.2 ± 2.0 weeks. In Twin 1, smaller GA (OR = 0.44, P = 0.02), higher mean oxygen concentration (OR = 1.34, P = 0.03), presence of thrombocytopenia (OR = 1429.60, P < 0.0001), and intraventricular hemorrhage (OR = 18.67, P = 0.03) were significant risk factors for ROP. For Twin 2, a smaller GA (OR = 0.45, P = 0.03) was the only risk factor. There were no significant risk factors for ROP in Twin 1 or Twin 2 on multivariate analysis. CONCLUSION: In Chinese twin pairs, smaller GA was the only common risk factor for ROP while Twin 1 was more susceptible to the postnatal risks for ROP.

Structural insights into the evolution of the RAG recombinase.

Adaptive immunity in jawed vertebrates relies on the assembly of antigen receptor genes by the recombination activating gene 1 (RAG1)-RAG2 (collectively RAG) recombinase in a reaction known as V(D)J recombination. Extensive biochemical and structural evidence indicates that RAG and V(D)J recombination evolved from the components of a RAG-like (RAGL) transposable element through a process known as transposon molecular domestication. This Review describes recent advances in our understanding of the functional and structural transitions that occurred during RAG evolution. We use the structures of RAG and RAGL enzymes to trace the evolutionary adaptations that yielded a RAG recombinase with exquisitely regulated cleavage activity and a multilayered array of mechanisms to suppress transposition. We describe how changes in modes of DNA binding, alterations in the dynamics of protein-DNA complexes, single amino acid mutations and a modular design likely enabled RAG family enzymes to survive and spread in the genomes of eukaryotes. These advances highlight the insight that can be gained from viewing evolution of vertebrate immunity through the lens of comparative genome analyses coupled with structural biology and biochemistry.

Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery.

Eukaryotic genomes contain domesticated genes from integrating viruses and mobile genetic elements. Among these are homologs of the capsid protein (known as Gag) of long terminal repeat (LTR) retrotransposons and retroviruses. We identified several mammalian Gag homologs that form virus-like particles and one LTR retrotransposon homolog, PEG10, that preferentially binds and facilitates vesicular secretion of its own messenger RNA (mRNA). We showed that the mRNA cargo of PEG10 can be reprogrammed by flanking genes of interest with Peg10's untranslated regions. Taking advantage of this reprogrammability, we developed selective endogenous encapsidation for cellular delivery (SEND) by engineering both mouse and human PEG10 to package, secrete, and deliver specific RNAs. Together, these results demonstrate that SEND is a modular platform suited for development as an efficient therapeutic delivery modality.

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination.

A whole-genome CRISPR/Cas9 screen identified ATP2A2, the gene encoding the Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2 protein, as being important for V(D)J recombination. SERCAs are ER transmembrane proteins that pump Ca2+ from the cytosol into the ER lumen to maintain the ER Ca2+ reservoir and regulate cytosolic Ca2+-dependent processes. In preB cells, loss of SERCA2 leads to reduced V(D)J recombination kinetics due to diminished RAG-mediated DNA cleavage. SERCA2 deficiency in B cells leads to increased expression of SERCA3, and combined loss of SERCA2 and SERCA3 results in decreased ER Ca2+ levels, increased cytosolic Ca2+ levels, reduction in RAG1 and RAG2 gene expression, and a profound block in V(D)J recombination. Mice with B cells deficient in SERCA2 and humans with Darier disease, caused by heterozygous ATP2A2 mutations, have reduced numbers of mature B cells. We conclude that SERCA proteins modulate intracellular Ca2+ levels to regulate RAG1 and RAG2 gene expression and V(D)J recombination and that defects in SERCA functions cause lymphopenia.

Incidence and Risk Factors of Retinopathy of Prematurity From 2 Neonatal Intensive Care Units in a Hong Kong Chinese Population.

PURPOSE: To determine the incidence and risk factors of retinopathy of prematurity (ROP) in very low birth weight (VLBW) preterm Chinese infants. DESIGN: Retrospective review. METHODS: Medical records were reviewed for all neonates screened for ROP between January 2007 and December 2012 in Hong Kong. Screening was offered to VLBW (≤1500 g) and/or preterm (gestation, ≤32 weeks) neonates using the Royal College of Ophthalmologists ROP guideline and the International Classification of ROP by 3 pediatric ophthalmologists. Maternal and neonatal covariates were analyzed using univariate and multivariable logistic regression analyses for both ROP and type 1 ROP. RESULTS: Of the 513 screened infants, the mean gestational age (GA) was 30.0 ± 2.5 weeks and the mean birth weight (BW) was 1232.6 ± 325.2 g. The incidence of ROP and type 1 ROP was 18.5% and 3.7%, respectively. In univariate analysis, a lighter BW, lower GA, blood transfusion, patent ductus arteriosus, nonsteroidal anti-inflammatory drug use, postnatal hypotension, inotropes usage, low Apgar scores, sepsis, mechanical ventilation, supplementary oxygen use, respiratory distress syndrome, anemia, surfactant use, and bronchopulmonary dysplasia were found to be associated with the development of both ROP and type 1 ROP (P < 0.05). In multivariable logistic regression analysis, BW, GA, and intraventricular hemorrhage were significant risk factors for ROP. Preeclampsia and eclampsia were the only protective factors for ROP development on multivariable logistic regression analysis (P = 0.02). CONCLUSIONS: In VLBW preterm Chinese infants, lower GA, lighter BW, and intraventricular hemorrhage were significant risk factors for ROP, whereas preeclampsia and eclampsia were protective.

Optimal selective laser trabeculoplasty energy for maximal intraocular pressure reduction in open-angle glaucoma.

PURPOSE: To identify the optimal energy level to be used in selective laser trabeculoplasty (SLT) for maximal intraocular pressure (IOP) reduction in open-angle glaucoma (OAG) patients. PATIENTS AND METHODS: This cohort sequentially recruited OAG subjects in Hong Kong, China during 2011 to 2012. All subjects received a single session of SLT with near confluent spots to 360 degrees of the trabecular meshwork. An initial energy of 0.8 mJ was titrated until bubble formation was just visible. The main outcomes included: change in IOP (pre-SLT to 1 mo post-SLT) and total SLT energy (SLT spots multiplied by the mean energy). For statistical analysis, only the right eye of each subject was used. Bandwidth selection by generalized cross-validation was used to determine the optimal interval and point of total SLT energy that resulted in the largest IOP reduction. RESULTS: A total of 49 Chinese OAG subjects had a mean age of 64.2±11.1 years. The pre-SLT IOP was 17.1±2.9 mm Hg while on 1.9±1.1 types of antiglaucoma eye drops. The mean total energy was 167.1±41.4 mJ (171.5±41.2 spots at 1.0±0.06 mJ). The 1 month post-SLT IOP was 13.5±2.8 mm Hg. The percentage of SLT success was 57.1% (28/49). The 95% confidence band by bootstrap method was plotted showing that a total energy between 214.6 and 234.9 mJ significantly decreased the IOP>25%, with the optimal total energy at 226.1 mJ. CONCLUSIONS: A higher SLT energy, in the range of 214.6 to 234.9 mJ, seems to be associated with an improved IOP-lowering response. Further randomized control trials with treatment stratification are needed to confirm these results.

Incidence and risk factors for retinopathy of prematurity in multiple gestations: a Chinese population study.

To determine the incidence and risk factors of retinopathy of prematurity (ROP) among new-born Chinese infants of multiple gestations.A retrospective review of medical records was performed for all neonates of multiple gestations screened for ROP between January 2007 and December 2012 in 2 neonatal intensive care units in Hong Kong. Screening was offered to very low birth weight (VLBW; ≤1500 g) and/or preterm (gestation ≤32 weeks) neonates using the Royal College of Ophthalmologists ROP guideline and the International Classification of ROP by 3 pediatric ophthalmologists. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP.A total of 153 Chinese infants of multiple gestations were included in the study. The mean gestational age (GA) was 30.8 ±â€Š2.4 weeks and the mean birth weight (BW) was 1284.8 ±â€Š267.4 g. The incidence of ROP and Type 1 ROP was 11.8% and 3.9%, respectively. On univariate analysis, younger GA, lighter birth weight, postnatal hypotension, inotropes use, bronchopulmonary disease, and intraventricular hemorrhage were common independent risk factors for the development of ROP and Type 1 ROP (all P ≤ 0.04). On multivariate analysis, younger GA, surfactant use, invasive mechanical ventilation, higher mean oxygen concentration, thrombocytopenia, intraventricular hemorrhage, total parental nutrition, and hypoglycemia were significant risk factors for ROP. For Type 1 ROP, there were no significant dependent risk factors.In preterm Chinese infants born from multiple gestations, prematurity, lighter weight, postnatal hypotension, inotropes use, bronchopulmonary dysplasia, and an intraventricular hemorrhage were common independent risk factors for the development of ROP and Type 1 ROP.

Predictors of success in selective laser trabeculoplasty for chinese open-angle glaucoma.

AIM: To investigate the determinants of success of selective laser trabeculoplasty (SLT) in Chinese open-angle glaucoma patients. METHODS: This prospective cohort study sequentially recruited Chinese subjects with unilateral or bilateral primary open-angle glaucoma (POAG) or normal tension glaucoma (NTG). All subjects received a single session of 360-degree SLT treatment. Success was defined as IOP reduction ≥20%. The following were analyzed in univariate and multivariate regression analyses for association with SLT success: type of glaucoma, age, sex, lens status, presenting IOP, pre-SLT IOP, day 1 IOP, 1-week IOP, number and type of anti-glaucoma medications, number of SLT shots and energy, retinal nerve fiber layer (RNFL) thickness, Visual Field Index, endothelial cell count, central corneal thickness, Snellen visual acuity, and spherical equivalent. RESULTS: In 111 eyes of 65 subjects, there were 51 POAG eyes and 60 NTG eyes. The overall success was 53.15% with a mean IOP reduction of 19.81±15.93%. In univariate analysis, a thinner RNFL [coefficient=-0.027; odds ratio (OR)=0.95; P=0.017] was associated with success. In multivariate analysis, a lower day 1 IOP (coefficient=-0.29; OR=0.75; P=0.049) and using topical carbonic anhydrase inhibitors (CAI) (coefficient=2.92; OR=18.63; P=0.0020) were associated with success. In both univariate and multivariate analyses, a higher pre-SLT IOP significantly predicted success (coefficient=0.20/0.46; OR=1.23/1.58; P=0.0017/0.0011) and using 3 anti-glaucoma medications (coefficient=-1.08/-3.74; OR=0.3/0.024; P=0.037/P=0.0081) was associated with SLT failure. CONCLUSION: The positive predictors of SLT success included: higher pre-SLT IOP, use of topical CAI, thinner RNFL, and lower day 1 IOP. Using 3 anti-glaucoma medications was associated with failure.

Predictors of success in selective laser trabeculoplasty for normal tension glaucoma.

To determine the predictors of success for selective laser trabeculoplasty (SLT) in normal tension glaucoma (NTG). This prospective cohort study recruited subjects with unilateral or bilateral NTG on medication. All subjects received a single session of 360° SLT treatment. SLT success was defined as IOP reduction≥20% at 1-month. The following covariates were analyzed via univariate and multivariate analyses: age; sex; lens status; presenting, pre-SLT, and post-SLT IOP's; number and type of medications; SLT shots and energy; and pre-SLT investigations. In 60 eyes of 32 subjects with NTG, there were 30 right eyes and 28 left eyes. The success rate of SLT was 61.7%. Using 3 types of anti-glaucoma medications (coefficient=-2.2, OR=0.1, P=0.02) and a thicker retinal nerve fiber layer thickness (coefficient=-0.04, OR=0.96, P=0.04) were associated with failure (univariate analysis). In multivariate analysis, a higher pre-SLT IOP (coefficient=1.1, OR=3.1, P=0.05) and a lower 1-week IOP (coefficient=-0.8, OR=0.5, P=0.04) were associated with success. SLT was successful in over 60% of treated NTG patients. A higher pre-SLT IOP and a greater IOP reduction at 1-week post-SLT were predictors of a successful outcome.

Risk factors for retinopathy of prematurity in extremely preterm Chinese infants.

To investigate the incidence and risk factors of retinopathy of prematurity (ROP) and Type 1 ROP in extremely preterm Chinese infants. A retrospective review of medical records was performed of all extremely preterm neonates (gestational age, GA≤28 weeks) screened for ROP from 2007 to 2012 at an ophthalmology centre in Hong Kong. Thirty-three maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. The mean gestational age (GA) was 26.4±1.3 weeks and the birth weight (BW) was 855.0±199.0 g. The incidence of ROP development was 60.7% and 16.2% for Type 1 ROP. On univariate analysis, 6 risk factors were identified for ROP development including: lighter BW; lower GA; postnatal hypotension; inotrope use; surfactant use; and invasive mechanical ventilation (all P≤0.01). On multivariate analysis, neonatal congenital heart disease and greater GA were protective factors for ROP development (P≤0.04). On the other hand, 4 risk factors were associated with Type 1 ROP development in univariate analysis, including: lower GA, lighter BW, multiple pregnancies, and invasive mechanical ventilation (all P≤0.02); while there was no significant risk factors on multivariate analysis. A lighter BW and lower GA were the only common independent risk factors for both ROP and Type 1 ROP while neonatal congenital heart disease and greater GA were the protective factors against ROP.